Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

Abstract

The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.

Iron Overload in Brain: Transport Mismatches, Microbleeding Events, and How Nanochelating Therapies May Counteract Their Effects

“…Then, deferiprone and deferasinox were introduced as iron-chelating drugs. The pharmacological and toxicological aspects of these three drugs have been widely investigated [98].…”

The Puzzle of Aspirin and Iron Deficiency: The Vital Missing Link of the Iron-Chelating Metabolites

“…In an attempt to solve the puzzle of the cause of iron deficiency in long-term, lowdose daily aspirin users, a major role in the iron-chelating activity of the ACM has been preliminarily proposed considering different parameters, including drug biotransformation and posology effects on iron absorption and iron excretion and overall iron chelation activity [86]. The observation that only a portion of the low-dose, long-term aspirin users develops iron deficiency is another parameter of the puzzle which needs further investigation.…”

“…A different mechanism of iron excretion involving aspirin and ACM is anticipated. In this case, most of the orally administered aspirin seems to be absorbed and metabolically converted to salicylic acid and the other metabolites, with, overall, more than 70% of aspirin associated with the biotransformation to ACM capable of mobilizing iron from different iron pools and causing an increase in iron excretion [7,51,86]. In particular, the mode of chelating activity of aspirin and the ACM resembles the widely used iron chelation combination therapy, where the combination of chelating drugs is more effective in increasing iron excretion than any monotherapy [55][56][57]86,108].…”

“…There are several other parameters to be considered regarding the concentration and efficacy of the ACMs. In contrast to chelating drugs such as oral deferiprone and deferasirox, which are rapidly transformed to glucuronide metabolites with no chelating properties, the ACMs are excreted in the urine with no further metabolic transformation (Figure 2) [80][81][82]86]. The drug posology administered, as well as the drug and, in this case, ACM concentration in the blood, are important parameters in determining the level of iron excretion during chelation therapy [86].…”

“…The connection between aspirin use and IDA has not yet been fully characterised. It has recently been suggested that some of the aspirin metabolites have iron-chelating properties (ACM) and may be involved in the cause of IDA [86]. It has also been suggested that the metabolism of aspirin to ACM resembles the cardioprotective chelating pro-drug dexrazoxane, which is metabolized to an EDTA-like chelator [86].…”